Methamphetamine continues to be a major drug of abuse associated with significant behavioral and physical toxicity. Work during the previous funding period has shown that dopamine partial agonists block the reinforcing actions of methamphetamine and block the reward deficits associated with methamphetamine withdrawal. Additional studies have characterized a progressive increase in methamphetamine selfadministration with extended access (escalation), and in preliminary studies treatment with dopamine partial agonists block the reinforcing effects of methamphetamine in the escalation model. The purpose of the present series of studies is to exploit the extended access (escalation) model to explore the effects of dopamine partial agonists and full direct agonists on various stages of the addiction cycle. Rats will be implanted with intravenous jugular catheters and trained to self-administer methamphetamine intravenously. Further characterization of the factors that promote escalation in intake with extended access (dose, time of session, intersession intervals and withdrawal) will be explored in Specific Aim 1. The effects of partial dopamine agonists on the increased self-administration observed during extended access to methamphetamine (escalation) will be explored in Specific Aim 2. The effects of dopamine partial agonists on reward deficits associated with withdrawal from extended access to methamphetamine will be explored in Specific Aim 3. The effects of prolonged access to methamphetamine self-administration on measure or neurotoxicity inducing dopamine levels, GFAP and immunocytochemistry measures of DAT and apoptosis and the effects of dopamine partial agonists will be explored in Specific Aim 4. The results of the proposed studies will not only provide novel insights into the neuropharmacological mechanisms of methamphetamine self-administration, but also will provide novel animal models and neuropharmacological data with which to assess potential medications for methamphetamine abuse and dependence.